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      Acid-cleavable thiomaleamic acid linker for homogeneous antibody–drug conjugation†

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          Abstract

          Homogeneous antibody–drug conjugation is affected using a novel thiomaleamic acid linker that is stable at physiological temperature and pH, but quantitatively cleaves at lysosomal pH to release the drug payload.

          Abstract

          In this communication we describe a novel acid-cleavable linker strategy for antibody–drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody–drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload.

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          Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes.

          Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.
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            Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius.

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              Marketed therapeutic antibodies compendium

              Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented here for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. Of the 34 mAbs, 28 (abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, tositumomab-I131, cetuximab, ibrituximab tiuxetan, omalizumab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, certolizumab pegol, golimumab, canakinumab, catumaxomab, ustekinumab, tocilizumab, ofatumumab, denosumab, belimumab, ipilimumab, brentuximab) are currently marketed in Europe or the US. Data for six therapeutic mAbs (muromonab-CD3, nebacumab, edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or discontinued from marketing in Europe or the US are also included.
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                Author and article information

                Journal
                Chem Commun (Camb)
                Chem. Commun. (Camb.)
                Chemical Communications (Cambridge, England)
                Royal Society of Chemistry
                1359-7345
                1364-548X
                21 June 2013
                9 August 2013
                : 49
                : 74
                : 8187-8189
                Affiliations
                [a ] Department of Chemistry , University College London , 20 Gordon Street , London , WC1H 0AJ , UK . Email: m.e.b.smith@ 123456ucl.ac.uk ; Email: vpenterprise@ 123456ucl.ac.uk ; Tel: +44 (0)20 7679 7538
                [b ] UCL Cancer Institute , 72 Huntley Street , London , WC1E 6BT , UK
                Article
                c3cc45220d
                10.1039/c3cc45220d
                3763782
                23929130
                505f70fd-7ccf-4a21-afc7-4328108131ce
                This journal is © The Royal Society of Chemistry 2013

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 July 2013
                : 2 August 2013
                Categories
                Chemistry

                Notes

                †Electronic supplementary information (ESI) available: 1H and 13C spectra for all novel compounds, and ES-MS spectra for all reactions with proteins described herein. See DOI: 10.1039/c3cc45220d


                General chemistry
                General chemistry

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